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| Item Type: | Preprint |
|---|---|
| Title: | Inheritance of old mitochondria controls early CD8(+) T cell fate commitment and is regulated by autophagy |
| Creators Name: | Borsa, M., Lechuga-Vieco, A.V., Kayvanjoo, A.H., Yazicioglu, Y., Compeer, E.B., Richter, F.C., Bui, H., Dustin, M.L., Katajisto, P. and Simon, A.K. |
| Abstract: | T cell immunity is impaired during ageing, particularly in memory responses needed for efficient vaccination. Autophagy and asymmetric cell division (ACD) are cell biological mechanisms key to memory formation, which undergo a decline upon ageing. However, despite the fundamental importance of these processes in cellular function, the link between ACD and in vivo fate decisions has remained highly correlative in T cells and in the field of mammalian ACD overall. Here we provide robust causal evidence linking ACD to in vivo T cell fate decisions and our data are consistent with the concept that initiation of asymmetric T cell fates is regulated by autophagy. Analysing the proteome of first-daughter CD8(+) T cells following TCR-triggered activation, we reveal that mitochondrial proteins rely on autophagy for their asymmetric inheritance and that damaged mitochondria are polarized upon first division. These results led us to evaluate whether mitochondria were asymmetrically inherited and to functionally address their impact on T cell fate. For this we used a novel mouse model that allows sequential tagging of mitochondria in mother and daughter cells, enabling their isolation and subsequent in vivo analysis of CD8(+) T cell progenies based on pre-mitotic cell cargo. Autophagy-deficient CD8(+) T cells showed impaired clearance and symmetric inheritance of old mitochondria, suggesting that degradation events promote asymmetry and are needed to generate T cells devoid of old organelles. Daughter cells inheriting old mitochondria are more glycolytic and upon adoptive transfer show reduced memory potential, whereas daughter cells that have not inherited old mitochondria from the mother cell are long-lived and expand upon cognate-antigen challenge. Proteomic and single-cell transcriptomic analysis of cells inheriting aged mitochondria suggest that their early fate divergence relies on one carbon metabolism as a consequence of poor mitochondrial quality and function. These findings increase our understanding of how T cell diversity is early-imprinted during division and will help foster the development of strategies to modulate T cell function. |
| Keywords: | Animals, Mice |
| Source: | bioRxiv |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Article Number: | 2024.01.29.577412 |
| Date: | 31 January 2024 |
| Official Publication: | https://doi.org/10.1101/2024.01.29.577412 |
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